PROJECT SUMMARY ABSTRACT As the successfully treated population of Human Immunodeficiency Virus (HIV)-infected individuals age, cognitive and health challenges of normal aging ensue, burdened by HIV, treatment side effects, and high prevalence comorbidities, notably, Alcohol Use Disorder (ALC) and hepatitis C virus (HCV). The aging brain is increasingly vulnerable to endogenous and exogenous insult which, coupled with HIV infection, can lead to HIV-Associated Neurocognitive Disorder (HAND) and sensorimotor disturbances. Our goal is to explicate the role of aging in magnetic resonance (MR)-detectable HIV pathology in the context of common comorbidities (ALC, HCV), while considering HIV-relevant variables (nutrition, medication adherence and toxicity, liver integrity). As common HIV-associated comorbidities of ALC and HCV may intensify inflammatory cascades and potentiate HIV pathology, a corollary aim is to consider whether circulating markers of inflammation (microbial dislocation, monocyte-related immune activation, peripheral cytokine elevations) corroborate proposed imaging markers of neuroinflammation. We will follow 140 participants from our existing cohort and recruit 100 new subjects, with a focus on older HIV-infected individuals, using MR metrics consistent with our longitudinal database. In keeping with the requirements of the RFA, we propose four specific aims: 1. Investigate the cross-sectional and longitudinal pattern of brain and cognitive changes in terms of disease and age trajectories using quantitative MR imaging and neurocognitive measures. 2. Identify factors that modify HIV disease trajectory, including age, sex, alcohol consumption, HCV and its treatment, nutrition, medication adherence and toxicity, and hepatic integrity. Exploratory factors include measures of depressive symptoms, fatigue, sleep quality, and impulsivity. 3. Establish evidence for neuroinflammatory markers using free water DTI and brain metabolites quantified by magnetic resonance spectroscopy. 4. Quantify the extent of postural instability and truncal tremor in relation to comorbid factors and normal or accelerated aging. Accomplishment of these aims will enhance understanding of factors contributing to age and disease- related cognitive decline, sensorimotor problems, and neurodegeneration. Convergent evidence from blood biomarkers (elevations in microbial dislocation, monocyte activation, and proinflammatory cytokines), MRS metabolites [myo-Inositol (mI), choline-containing compounds (Cho), macromolecules (MM09+Lip09] and glutathione (GSH)], and DTI metrics (free water) may provide initial support for a constellation of in vivo markers of neuroinflammation.